Acute Myelogenous LeukemiaPhase 1NCT02319369

Safety, Tolerability and Pharmacokinetics of Milademetan Alone and With 5-Azacitidine (AZA) in Acute Myelogenous Leukemia (AML) or High-Risk Myelodysplastic Syndrome (MDS)

A Phase 1 study testing Milademetan and AZA in people with Acute Myelogenous Leukemia and Myelodysplastic Syndrome, run by Daiichi Sankyo at 5 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial summary

This study will take place in parts: Dose Escalation (Part 1): Participants receive milademetan alone with different dose schedules Dose Escalation (Part 1A): Participants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules The recommended dose for Part 2 will be selected. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Acute Myelogenous Leukemia, Myelodysplastic Syndrome
What is being tested?: Milademetan and AZA
Type of treatment: Pill or oral medicine, Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 74 participants
Where: 5 sitesUnited States
Study dates: 25 Nov 2014to 21 Aug 2020
Phase: Phase 1
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Has a diagnosis of refractory or relapsed (R/R) AML or high-risk MDS:
Part 1 and 1A (Dose Escalation)
Participants with R/R AML, OR
Participants with untreated, high-risk MDS or participants who have received prior MDS treatment regimens.
Participants ≥18 years old.
Part 2 (Dose Expansion)

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Cohort 1: R/R AML
Participants who have treatment failure to prior AML therapy or have relapsed after prior AML therapy.
Participants ≥18 years old.
Cohort 2: Newly diagnosed AML
Participants with newly diagnosed AML who are ineligible for intensive induction chemotherapy. Participants must have had no prior AML treatment, with the exceptions of therapy for antecedent hematologic malignancies or hydroxyurea.
Participants ≥75 years old, OR Participants between 18 and 74 years old (inclusive) with at least one of the specific protocol-defined comorbidities.
Cohort 3: High-risk MDS
Participants with untreated, high-risk MDS or who received up to 2 prior MDS treatment regimens.
Has an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
As an exception, participants with newly diagnosed AML between 18 and 74 years old (inclusive) in Part 2 Cohort 2 with ECOG Performance Status of 3 will be eligible.
Has protocol-defined adequate renal, hepatic and blood clotting functions.
Is able to provide written informed consent (or authorized representative), comply with protocol visits and procedures, and take oral medication, and does not have any active infection or comorbidity that would interfere with therapy.
If female, is either postmenopausal (no menstrual period for a minimum of 12 months), surgically sterile, or, if of childbearing potential, has a negative serum pregnancy test upon entry into this study and is willing to use maximally effective birth control during the period of therapy and for 6 months following the last investigational drug dose.
If male, is surgically sterile or willing to use a maximally effective double-barrier contraception method upon enrollment, during the course of the study, and for 6 months following the last investigational drug dose.
Is fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects).
Signs and dates an Institutional Review Board-approved informed consent form (including Health Insurance Portability and Accountability Act authorization, if applicable) before performance of any study-specific procedures or tests.
Is able and willing to provide bone marrow biopsies/aspirates as requested by the protocol.
Is willing to undergo malignancy genotyping for TP53 mutation, insertion, or deletion at screening.

Who cannot join

Has a diagnosis of acute promyelocytic leukemia.
Has a malignancy that is known to contain a non-synonymous mutation, insertion, or deletion in the TP53 gene determined previously or at screening.
Has presence of central nervous system (CNS) involvement of leukemia or a history of primary CNS leukemia.
Has a second concurrent primary malignancy that required active treatment within the previous 2 years, except for localized cancers that have apparently been cured, such as non-melanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast.
Has any condition that would preclude adequate absorption of DS-3032b, including refractory nausea and vomiting, malabsorption, biliary shunt, significant bowel resection, and/or graft-versus-host disease (GVHD) affecting the gut.
Has an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, known human immunodeficiency virus infection, or active hepatitis B or C infection.

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Has a concomitant medical condition that would increase the risk of toxicity.
Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE Grade ≤ 1, or baseline. Subjects with chronic Grade 2 toxicities may be eligible at the discretion of the Investigator and Sponsor (eg, Grade 2 chemotherapy-induced neuropathy).
Has received Hematopoietic Stem Cell Transplantation (HSCT) within 60 days of the first dose of study drugs or has clinically significant GVHD or GVHD requiring initiation of systemic treatment or systemic treatment escalation within 21 days prior to Screening and/or >Grade 1 persistent or clinically significant GVHD or other non-hematologic toxicity related to HCT.
Is receiving concomitant treatment with a strong inhibitor or inducer of cytochrome P450 3A4/5.
Has received any therapies intended to treat malignancy within 7 days (small molecules) or 21 days (anti-body/immune based biologics) of first receipt of study drugs [except for hydroxyurea, which must be discontinued at least 48 hours (Day -2) prior to study treatment].
Had major surgery within 4 weeks prior to study drug treatment.
Participated in a therapeutic clinical study within a washout time of 2 weeks or 5 half-lives of the drug/biologic (whichever is longer) before starting study drug treatment under this protocol, or current participation in other therapeutic investigational procedures.
Has prolongation of corrected QT interval using Fridericia's method (QTcF) at rest, where the mean QTcF interval is > 480 ms based on triplicate electrocardiograms (ECGs).
Is pregnant or breastfeeding.
Has substance abuse or medical, psychological, or social conditions that, in the opinion of the Investigator, may interfere with the subject's participation in the clinical study or evaluation of the clinical study results.
Prior treatment with an MDM2 inhibitor.

Trial locations and contacts

5 sites in 1 country.

City, postcode or hospital

5 sites in 1 country

United States5 sites

Roswell Park Comprehensive Cancer Center
Buffalo, New York, 14263
City of Hope National Medical Center
Duarte, California, 91010
University of Kansas Cancer Center
Fairway, Kansas, 66205
M D Anderson Cancer Center
Houston, Texas, 77031
University of California San Francisco Medical Center
San Francisco, California, 94143

Other trials in United States

About this study

Official title: A Phase 1 Study of Milademetan (DS 3032b), an Oral MDM2 Inhibitor, In Dose Escalation as a Single Agent and In Dose Escalation/Expansion In Combination With 5 Azacitidine In Subjects With Acute Myelogenous Leukemia (AML) or High Risk Myelodysplastic Syndrome (MDS)

This study will take place in parts:

Dose Escalation (Part 1): Participants receive milademetan alone with different dose schedules
Dose Escalation (Part 1A): Participants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules

The recommended dose for Part 2 will be selected.

Dose Expansion (Part 2): After Part 1A, participants will receive the recommended Part 2 dose schedule. There will be three groups - those with:

refractory or relapsed acute myelogenous leukemia (AML)
newly diagnosed AML unfit for intensive chemotherapy
high-risk myelodysplastic syndrome (MDS)

End-of-Study Follow-Up: Safety information will be collected until 30 days after the last treatment. This is the end of the study.

The recommended dose for the next study will be selected.

Read the detailed description

The primary analysis will occur after all participants have either discontinued the study or completed at least 6 months of treatment. After the primary analysis, the main study will be closed. Participants who are still on study at least 6 months after enrollment of the last participant in the study may be eligible to continue receiving study drug in a separate extension phase of the protocol

Conditions: Acute Myelogenous Leukemia, Myelodysplastic Syndrome
Being tested: Milademetan, AZA
Keywords: High Risk Myelodysplastic Syndrome, Relapsed/Refractory, Newly Diagnosed, Unfit for Chemotherapy
Medical subject headings: Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Recurrence

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

MilademetanDrug
Also called Oral MDM2 Inhibitor
Milademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5 mg, 20 mg, 80 mg, and/or 200 mg
AZADrug
Also called 5-Azacitidine
AZA will be administered at 75 mg/m^2 subcutaneously or intravenously
MilademetanDrug
Also called Oral MDM2 Inhibitor
Milademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5, 20, 80, and/or 200 mg. An alternate combination of 30 mg, 80 mg, and/or 100 mg milademetan may be utilized.

Study groups in NCT02319369
Study group	Role	What they receive
Part 1, Milademetan Alone	Experimental	Participants receive milademetan alone with different dose schedules Receives: Drug: Milademetan
Part 1A, Milademetan with 5-azacytidine (AZA)	Experimental	Participants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules Receives: Drug: Milademetan; Drug: AZA
Part 2, Cohort 1	Experimental	Participants with refractory or relapsed acute myelogenous leukemia (AML) receive the recommended dose for Part 2 of milademetan or milademetan with5-azacytidine (AZA) Receives: Drug: AZA; Drug: Milademetan
Part 2, Cohort 2	Experimental	Participants with newly diagnosed acute myelogenous leukemia (AML) unfit for intensive chemotherapy receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA) Receives: Drug: AZA; Drug: Milademetan
Part 2, Cohort 3	Experimental	Participants with high-risk myelodysplastic syndrome (MDS) receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA) Receives: Drug: AZA; Drug: Milademetan

What is being measured

The primary outcome is the main question the study is designed to answer.

Number of Participants With Dose-Limiting Toxicities (DLTs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA)
A DLT was defined as any treatment-emergent adverse event not attributable to disease or disease-related processes occurring during the observation period (Cycle 1) in each dose-level cohort and is Grade (Gr) 3 or higher according to NCI CTCAE Version 5.0 (Version 4.03 before 01 Apr 2018), with these exceptions: for elevations in hepatic function enzymes, a DLT is defined as: Gr ≥3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels lasting >3 days; AST/ALT >5 × ULN if accompanied by ≥Gr 2 elevation in bilirubin. Potential DLTs include: Participants who are unable to complete at least 75% of milademetan or AZA in Cycle 1 as a result of non-disease-related Gr ≥2 events; Persistent bone marrow aplasia in the absence of malignant cell infiltration, and failure to recover a peripheral absolute neutrophil count ≥0.5 × 10^9/L and platelets ≥20 × 10^9/L while withholding study drug, resulting in >2-week delay in initiating Cycle 2.
Measured: From the date the participant signed the informed consent form up to 5 years of first participant enrolled
Number of Participants (≥10%) With Treatment-emergent Adverse Events (TEAEs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA)
A treatment-emergent adverse event (TEAE) is defined as an adverse event that emerges during the treatment period (up to 30 days after last dose), having been absent at pre-treatment; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-treatment state, when the adverse event is continuous.
Measured: From the date the participant signed the informed consent form up to 30 days after the last dose in the last participant, up to approximately 6 years of first participant enrolled

Secondary outcomes (9)

Maximum Plasma Concentration (Cmax) Following Administration of Milademetan Alone
Pharmacokinetic parameter maximum plasma concentration (Cmax) of milademetan was assessed at select time points and the geometric means (coefficient of variation %) are presented.
Measured: Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days)
Maximum Plasma Concentration (Cmax) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)
Pharmacokinetic parameter maximum plasma concentration (Cmax) was assessed at select time points and the geometric means (coefficient of variation %) are presented.
Measured: Predose, 0.5 hour (hr), 1 hr, 2 hr, 3 hr, 6 hr of Cycle 1, Day 1 (AZA); Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Day 5, Day 7 (predose) (Cohorts 10e and 12e), Day 8 (Cohorts 11f and 13f), and Day 14 (Cohorts 10e-13f) (each cycle is 28 days)
Time to Maximum Concentration (Tmax) Following Administration of Milademetan Alone
Pharmacokinetic parameter time to maximum concentration (Tmax) of milademetan was assessed at select time points.
Measured: Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days)
Time to Maximum Concentration (Tmax) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)
Pharmacokinetic parameter time to maximum concentration (Tmax) was assessed at select time points.
Measured: Predose, 0.5 hour (hr), 1 hr, 2 hr, 3 hr, 6 hr of Cycle 1, Day 1 (AZA); Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Day 5, Day 7 (predose) (Cohorts 10e and 12e), Day 8 (Cohorts 11f and 13f), and Day 14 (Cohorts 10e-13f) (each cycle is 28 days)
Trough Plasma Concentration (Ctrough) Following Administration of Milademetan Alone
Pharmacokinetic parameter plasma concentration before next dose (Ctrough) of milademetan was assessed at Cycle 1, Day 15 and the geometric means (coefficient of variation %) are presented.
Measured: Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days)
Area Under the Plasma Concentration Curve up to 24 Hours (AUC0-24) Following Administration of Milademetan Alone
Pharmacokinetic parameter area under the plasma concentration curve up to 24 hours (AUC0-24) of milademetan was assessed at select time points and the geometric means (coefficient of variation %) are presented.
Measured: Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days)
Area Under the Plasma Concentration Curve up to 24 Hours (AUC0-24) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)
Pharmacokinetic parameter area under the plasma concentration curve up to 24 hours (AUC0-24) was assessed at select time points and the geometric means (coefficient of variation %) are presented.
Measured: Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Cycle 1, Day 5 (Cohorts 10e and 12e) and Predose of Cycle 1, Day 14 (Cohorts 10e, 11f, and 12e) (each cycle is 28 days)
Serum Macrophage Inhibitory Cytokine-1 (MIC-1) Fold Change From Baseline Following Administration of Milademetan Alone
Pharmacodynamic biomarker serum macrophage inhibitory cytokine-1 (MIC-1) concentrations of milademetan were assessed for Cohorts 1 though 9d. Fold change is the ratio of post-baseline MIC-1 values with respect to the baseline values and is the measure of change of MIC-1 from baseline.
Measured: Day 1 (6 hours postdose) up to Day 21-22 (predose), up to approximately 6 years of first participant enrolled
Serum Macrophage Inhibitory Cytokine-1 (MIC-1) Fold Change From Baseline Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)
Pharmacodynamic biomarker serum macrophage inhibitory cytokine-1 (MIC-1) concentrations were assessed for Cohorts 10e though 13f. Fold change is the ratio of post-baseline MIC-1 values with respect to the baseline values and is the measure of change of MIC-1 from baseline.
Measured: Day 5 (predose) up to Day 22 (predose), up to approximately 6 years of first participant enrolled

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

25 Nov 201421 Aug 2020

First posted18 Dec 2014 (estimated)
Study start25 Nov 2014
Primary completion21 Aug 2020
Study completion21 Aug 2020

Why it stopped: This study was terminated based on a business decision by the Sponsor.

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Acute Myelogenous LeukemiaStudies of the same condition, open and under way.
More trials run by Daiichi SankyoThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Sequential
Model description: Parts 1 and 1A are sequential, then Part 2 is parallel
Masking: None (open label)
Enrolment: 74 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT02319369
Sponsor's protocol ID: DS3032-A-U102
Status last verified: Sep 2021
First submitted: 15 Dec 2014
Last updated: 11 Oct 2021
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No
FDA-regulated drug: Yes
FDA-regulated device: No
Individual data sharing: Yes: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

Publications

DiNardo CD, Olin R, Wang ES, Skikne B, Rosenthal J, Kumar P, Sumi H, Hizukuri Y, Hong Y, Patel P, Seki T, Duan T, Lesegretain A, Andreeff M. Phase 1 dose escalation study of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine in patients with myeloid malignancies. Cancer Med. 2024 Jul;13(14):e70028. doi: 10.1002/cam4.70028.
PubMed 39030997

Want to know more?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See locations

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Study at a glance

From the registry record, last updated by the sponsor on 11 Oct 2021. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase 1 Study of Milademetan (DS 3032b), an Oral MDM2 Inhibitor, In Dose Escalation as a Single Agent and In Dose Escalation/Expansion In Combination With 5 Azacitidine In Subjects With Acute Myelogenous Leukemia (AML) or High Risk Myelodysplastic Syndrome (MDS)
ClinicalTrials.gov ID: NCT02319369
Acronym / sponsor ID: DS3032-A-U102
Conditions: Acute Myelogenous Leukemia, Myelodysplastic Syndrome
Keywords: High Risk Myelodysplastic Syndrome, Relapsed/Refractory, Newly Diagnosed, Unfit for Chemotherapy
Phase: Phase 1
Study type: Interventional
Recruitment status: TerminatedReason stopped: This study was terminated based on a business decision by the Sponsor.
Enrolment: 74 participants (actual)
Lead sponsor: Daiichi SankyoIndustry (pharma, biotech, devices)
Study start: 25 Nov 2014 (actual)
Primary completion: 21 Aug 2020 (actual)
Study completion: 21 Aug 2020 (actual)
First posted: 18 Dec 2014 (estimated)
Results: Posted 11 Oct 2021

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

This study will take place in parts:

Dose Escalation (Part 1): Participants receive milademetan alone with different dose schedules
Dose Escalation (Part 1A): Participants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules

The recommended dose for Part 2 will be selected.

Dose Expansion (Part 2): After Part 1A, participants will receive the recommended Part 2 dose schedule. There will be three groups - those with:

refractory or relapsed acute myelogenous leukemia (AML)
newly diagnosed AML unfit for intensive chemotherapy
high-risk myelodysplastic syndrome (MDS)

End-of-Study Follow-Up: Safety information will be collected until 30 days after the last treatment. This is the end of the study.

The recommended dose for the next study will be selected.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Sequential
Masking: None (open label)
Number of arms: 5
Model description: Parts 1 and 1A are sequential, then Part 2 is parallel

Arm	Type	Receives
Part 1, Milademetan Alone	Experimental	Drug: MilademetanParticipants receive milademetan alone with different dose schedules
Part 1A, Milademetan with 5-azacytidine (AZA)	Experimental	Drug: Milademetan, Drug: AZAParticipants receive milademetan in combination with 5-azacytidine (AZA), with different dose schedules
Part 2, Cohort 1	Experimental	Drug: AZA, Drug: MilademetanParticipants with refractory or relapsed acute myelogenous leukemia (AML) receive the recommended dose for Part 2 of milademetan or milademetan with5-azacytidine (AZA)
Part 2, Cohort 2	Experimental	Drug: AZA, Drug: MilademetanParticipants with newly diagnosed acute myelogenous leukemia (AML) unfit for intensive chemotherapy receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA)
Part 2, Cohort 3	Experimental	Drug: AZA, Drug: MilademetanParticipants with high-risk myelodysplastic syndrome (MDS) receive the recommended dose for Part 2 of milademetan or milademetan with 5-azacytidine (AZA)

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (24 listed)

Has a diagnosis of refractory or relapsed (R/R) AML or high-risk MDS:
Has an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
Has protocol-defined adequate renal, hepatic and blood clotting functions.
Is able to provide written informed consent (or authorized representative), comply with protocol visits and procedures, and take oral medication, and does not have any active infection or comorbidity that would interfere with therapy.
If female, is either postmenopausal (no menstrual period for a minimum of 12 months), surgically sterile, or, if of childbearing potential, has a negative serum pregnancy test upon entry into this study and is willing to use maximally effective birth control during the period of therapy and for 6 months following the last investigational drug dose.

Key exclusion criteria (17 listed)

Has a diagnosis of acute promyelocytic leukemia.
Has a malignancy that is known to contain a non-synonymous mutation, insertion, or deletion in the TP53 gene determined previously or at screening.
Has presence of central nervous system (CNS) involvement of leukemia or a history of primary CNS leukemia.
Has a second concurrent primary malignancy that required active treatment within the previous 2 years, except for localized cancers that have apparently been cured, such as non-melanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast.
Has any condition that would preclude adequate absorption of DS-3032b, including refractory nausea and vomiting, malabsorption, biliary shunt, significant bowel resection, and/or graft-versus-host disease (GVHD) affecting the gut.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
MilademetanAlso: Oral MDM2 InhibitorMilademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5 mg, 20 mg, 80 mg, and/or 200 mg	Drug	Part 1, Milademetan Alone, Part 1A, Milademetan with 5-azacytidine (AZA)
AZAAlso: 5-AzacitidineAZA will be administered at 75 mg/m^2 subcutaneously or intravenously	Drug	Part 1A, Milademetan with 5-azacytidine (AZA), Part 2, Cohort 1, Part 2, Cohort 2, Part 2, Cohort 3
MilademetanAlso: Oral MDM2 InhibitorMilademetan will be administered daily as oral capsules or as a combination of multiple oral capsules containing 5, 20, 80, and/or 200 mg. An alternate combination of 30 mg, 80 mg, and/or 100 mg milademetan may be utilized.	Drug	Part 2, Cohort 1, Part 2, Cohort 2, Part 2, Cohort 3

Primary outcome

Number of Participants With Dose-Limiting Toxicities (DLTs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA)
Time frame: From the date the participant signed the informed consent form up to 5 years of first participant enrolled
A DLT was defined as any treatment-emergent adverse event not attributable to disease or disease-related processes occurring during the observation period (Cycle 1) in each dose-level cohort and is Grade (Gr) 3 or higher according to NCI CTCAE Version 5.0 (Version 4.03 before 01 Apr 2018), with these exceptions: for elevations in hepatic function enzymes, a DLT is defined as: Gr ≥3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) levels lasting >3 days; AST/ALT >5 × ULN if accompanied by ≥Gr 2 elevation in bilirubin. Potential DLTs include: Participants who are unable to complete at least 75% of milademetan or AZA in Cycle 1 as a result of non-disease-related Gr ≥2 events; Persistent bone marrow aplasia in the absence of malignant cell infiltration, and failure to recover a peripheral absolute neutrophil count ≥0.5 × 10^9/L and platelets ≥20 × 10^9/L while withholding study drug, resulting in >2-week delay in initiating Cycle 2.
Number of Participants (≥10%) With Treatment-emergent Adverse Events (TEAEs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA)
Time frame: From the date the participant signed the informed consent form up to 30 days after the last dose in the last participant, up to approximately 6 years of first participant enrolled
A treatment-emergent adverse event (TEAE) is defined as an adverse event that emerges during the treatment period (up to 30 days after last dose), having been absent at pre-treatment; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-treatment state, when the adverse event is continuous.

9 secondary outcomes

Maximum Plasma Concentration (Cmax) Following Administration of Milademetan Alone
Time frame: Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days)
Maximum Plasma Concentration (Cmax) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)
Time frame: Predose, 0.5 hour (hr), 1 hr, 2 hr, 3 hr, 6 hr of Cycle 1, Day 1 (AZA); Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Day 5, Day 7 (predose) (Cohorts 10e and 12e), Day 8 (Cohorts 11f and 13f), and Day 14 (Cohorts 10e-13f) (each cycle is 28 days)
Time to Maximum Concentration (Tmax) Following Administration of Milademetan Alone
Time frame: Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days)
Time to Maximum Concentration (Tmax) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)
Time frame: Predose, 0.5 hour (hr), 1 hr, 2 hr, 3 hr, 6 hr of Cycle 1, Day 1 (AZA); Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Day 5, Day 7 (predose) (Cohorts 10e and 12e), Day 8 (Cohorts 11f and 13f), and Day 14 (Cohorts 10e-13f) (each cycle is 28 days)
Trough Plasma Concentration (Ctrough) Following Administration of Milademetan Alone
Time frame: Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days)
Area Under the Plasma Concentration Curve up to 24 Hours (AUC0-24) Following Administration of Milademetan Alone
Time frame: Predose, 1 hour (hr), 2 hr, 3 hr, 6 hr, 8 hr, 10 hr of Cycle 1, Day 1 (Cohorts 1-9d) and Cycle 1, Day 15 (Cohorts 1-5 and 7c) (each cycle is 28 days)
Area Under the Plasma Concentration Curve up to 24 Hours (AUC0-24) Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)
Time frame: Predose, 0.5 hr, 1 hr, 2 hr, 3 hr, 4 hr, 6-10 hr of Cycle 1, Day 5 (Cohorts 10e and 12e) and Predose of Cycle 1, Day 14 (Cohorts 10e, 11f, and 12e) (each cycle is 28 days)
Serum Macrophage Inhibitory Cytokine-1 (MIC-1) Fold Change From Baseline Following Administration of Milademetan Alone
Time frame: Day 1 (6 hours postdose) up to Day 21-22 (predose), up to approximately 6 years of first participant enrolled
Serum Macrophage Inhibitory Cytokine-1 (MIC-1) Fold Change From Baseline Following Administration of Milademetan In Combination With 5-Azacitidine (AZA)
Time frame: Day 5 (predose) up to Day 22 (predose), up to approximately 6 years of first participant enrolled

Results and safety

Results posted to the registry on 11 Oct 2021, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Cohort 1: Milademetan 60 mg	7	7
Cohort 2: Milademetan 90 mg	6	6
Cohort 3: Milademetan 120 mg	11	11
Cohort 4: Milademetan 160 mg	8	8
Cohort 5: Milademetan 210 mg	5	5
Cohort 6b: Milademetan 160 mg	7	7
Cohort 7c: Milademetan 160 mg	3	3
Cohort 8d: Milademetan 160 mg	6	6
Cohort 9d: Milademetan 220 mg	4	4
Cohort 10e: Milademetan 160 mg + Azacitidine 75 mg/m^2	9	9
Cohort 11f: Milademetan 160 mg + Azacitidine 75 mg/m^2	3	3
Cohort 12e: Milademetan 200 mg + Azacitidine 75 mg/m^2	4	4
Cohort 13f: Milademetan 200 mg + Azacitidine 75 mg/m^2	1	1

Primary outcome: Number of Participants With Dose-Limiting Toxicities (DLTs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA)

Time frame: From the date the participant signed the informed consent form up to 5 years of first participant enrolled. Count of participants. Unit: Participants

Measure	Cohort 1: Milademetan 60 mg n = 5	Cohort 4: Milademetan 160 mg n = 8	Cohort 5: Milademetan 210 mg n = 5	Cohort 9d: Milademetan 220 mg n = 3	Cohort 12e: Milademetan 200 mg + Azacitidine 75 mg/m^2 n = 4
Participants with TEAEs classified as DLTs	1	2	3	2	2
Nausea	0	0	1	2	0
Fatigue	0	0	1	0	2
Cellulitis	0	0	1	0	0
Diarrhoea	0	1	0	0	0
Hypokalaemia	0	1	0	0	0
Renal failure	0	0	1	0	0
Vomiting	1	0	0	0	0

Population analysed: Dose-limiting toxicities were reported in the DLT evaluable set for Cohorts 1, 4, 5, and 9d of Part 1 and Cohort 12e of Part 1a.

Primary outcome: Number of Participants (≥10%) With Treatment-emergent Adverse Events (TEAEs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA)

Time frame: From the date the participant signed the informed consent form up to 30 days after the last dose in the last participant, up to approximately 6 years of first participant enrolled. Count of participants. Unit: Participants

Measure	Cohort 1: Milademetan 60 mg n = 7	Cohort 2: Milademetan 90 mg n = 6	Cohort 3: Milademetan 120 mg n = 11	Cohort 4: Milademetan 160 mg n = 8	Cohort 5: Milademetan 210 mg n = 5	Cohort 6b: Milademetan 160 mg n = 7	Cohort 7c: Milademetan 160 mg n = 3	Cohort 8d: Milademetan 160 mg n = 6	Cohort 9d: Milademetan 220 mg n = 4	Cohort 10e: Milademetan 160 mg + Azacitidine 75 mg/m^2 n = 9	Cohort 11f: Milademetan 160 mg + Azacitidine 75 mg/m^2 n = 3	Cohort 12e: Milademetan 200 mg + Azacitidine 75 mg/m^2 n = 4	Cohort 13f: Milademetan 200 mg + Azacitidine 75 mg/m^2 n = 1
Any TEAEs	7	6	11	8	5	7	3	6	4	9	3	4	1
Nausea	5	4	8	6	4	3	2	4	3	5	2	2	1
Diarrhoea	2	2	8	5	3	4	2	3	3	1	2	1	0
Vomiting	2	1	4	4	3	2	2	3	3	3	2	0	0
Fatigue

9 secondary outcomes are reported in the full results.

Adverse events

Time frame: Treatment-emergent adverse events (TEAEs) were collected from the date the participant signed the informed consent form up to 30 days after the last dose of study drug, up to approximately 6 years of first participant enrolled.. Other adverse events reported at 5% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Cohort 1: Milademetan 60 mg	4 of 7 (57.1%)	7 of 7 (100%)	1 of 7
Cohort 2: Milademetan 90 mg	5 of 6 (83.3%)	6 of 6 (100%)	0 of 6
Cohort 3: Milademetan 120 mg	9 of 11 (81.8%)	11 of 11 (100%)	1 of 11
Cohort 4: Milademetan 160 mg	5 of 8 (62.5%)	8 of 8 (100%)	1 of 8
Cohort 5: Milademetan 210 mg	5 of 5 (100%)	5 of 5 (100%)	1 of 5
Cohort 6b: Milademetan 160 mg	4 of 7 (57.1%)	7 of 7 (100%)	1 of 7
Cohort 7c: Milademetan 160 mg	2 of 3 (66.7%)	3 of 3 (100%)	1 of 3
Cohort 8d: Milademetan 160 mg	3 of 6 (50%)	6 of 6 (100%)	1 of 6
Cohort 9d: Milademetan 220 mg	2 of 4 (50%)	4 of 4 (100%)	2 of 4
Cohort 10e: Milademetan 160 mg + Azacitidine 75 mg/m^2	9 of 9 (100%)	9 of 9 (100%)	2 of 9
Cohort 11f: Milademetan 160 mg + Azacitidine 75 mg/m^2	3 of 3 (100%)	3 of 3 (100%)	2 of 3
Cohort 12e: Milademetan 200 mg + Azacitidine 75 mg/m^2	4 of 4 (100%)	4 of 4 (100%)	1 of 4
Cohort 13f: Milademetan 200 mg + Azacitidine 75 mg/m^2	0 of 1 (0%)	1 of 1 (100%)	0 of 1

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 11 Oct 2021.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
Derived from this study: PubMed 39030997DiNardo CD, Olin R, Wang ES, Skikne B, Rosenthal J, Kumar P, Sumi H, Hizukuri Y, Hong Y, Patel P, Seki T, Duan T, Lesegretain A, Andreeff M. Phase 1 dose escalation study of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine in patients with myeloid malignancies. Cancer Med. 2024 Jul;13(14):e70028. doi: 10.1002/cam4.70028.
Individual participant dataSharing planned: Yes. De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Global Clinical Leader study director

Daiichi Sankyo

5 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Milademetan and AZA in people with Acute Myelogenous Leukemia and Myelodysplastic Syndrome, run by Daiichi Sankyo at 5 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 24 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 11 Oct 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 5 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 11 Oct 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Dose-Limiting Toxicities (DLTs) Following Administration of Milademetan Alone and In Combination With 5-Azacitidine (AZA) (time frame: From the date the participant signed the informed consent form up to 5 years of first participant enrolled). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02319369, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Oct 2021.